Abstract
BackgroundIt is increasingly being realized that failure of pancreatic beta cells to secrete enough insulin to adequately compensate for obesity and insulin resistance is the primary defects of type 2 diabetes mellitus (T2DM). Pancreatic beta cells possess a highly developed and active endoplasmic reticulum (ER), reflecting their role in folding, export and processing of newly synthesized insulin. ER stress-induced pancreatic beta-cell failure is a novel event in the pathogenesis of T2DM. Some studies with antioxidants indicated a beneficial impact on ER stress. Our previous study found that strong antioxidants, grape seed proanthocyanidins (GSPs), ameliorated ER stress to protect skeletal muscle from cell death in type 2 diabetic rats. The present study continued to investigate the effect of GSPs on beta-cell failure and ER stress in diabetic pancreas.MethodsMale Sprague–Dawley rats made type 2 diabetic with 2 injections of 25 mg/kg streptozotocin and 8 weeks of the high-carbohydrate/high-fat diet were fed a basal diet with or without GSPs administration for 16 weeks. Oral glucose tolerance, plasma glucose, serum insulin and the score of beta-cell function were measured. Morphological observation was performed by light and electron microscopic analyses. Islet cell apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling staining. Additionally, the level of insulin and the expression of ER stress markers in pancreatic islets were also studied using immunohistochemical staining.ResultsAfter 16 weeks treatment, the score of beta-cell function and the abnormal oral glucose tolerance of diabetic rats were partially reversed by GSPs treatment. The efficacious effect of GSPs was also manifested in the amelioration of pancreatic damage and ER dilatation by microscopic analyses. Moreover, GSPs treatment increased normal insulin content and decreased the number of apoptotic cells in diabetic islets. Importantly, GSPs treatment partially alleviated ER stress by decreasing some ER stress markers.ConclusionThese findings suggest that GSPs might have auxiliary therapeutic potential for pancreatic beta-cell dysfunction and death in T2DM.
Highlights
It is increasingly being realized that failure of pancreatic beta cells to secrete enough insulin to adequately compensate for obesity and insulin resistance is the primary defects of type 2 diabetes mellitus (T2DM)
Effect of grape seed proanthocyanidins (GSPs) on pancreas weight and pancreas/body weight (BW) ratio As shown in Table 1, there were no significant differences in pancreas weight and pancreas/BW ratio between normal and GSPs control groups
Apart from hyperglycemia and blood lipid disorder, we provided evidence of swollen endoplasmic reticulum (ER) and induction of glucose regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), Jun N terminal kinase (JNK) and Caspase-12 in diabetic beta cells, which are predominately regulated under conditions of severe and prolonged ER stress
Summary
It is increasingly being realized that failure of pancreatic beta cells to secrete enough insulin to adequately compensate for obesity and insulin resistance is the primary defects of type 2 diabetes mellitus (T2DM). It is increasingly being realized that failure of pancreatic beta cells to secrete enough insulin to adequately compensate for obesity and insulin resistance is the primary defects of T2DM [4,5]. Pancreatic beta cells possess a highly developed and active endoplasmic reticulum (ER), reflecting their role in folding, export and processing of newly synthesized insulin [6] Certain conditions, such as high lipid load, hyperglycemia, oxidative stress, excessive Ca2+ release from ER stores, or misfolded mutant insulin proteins, will disrupt ER homeostasis, resulting in an adaptive unfolded protein response (UPR), which aims to restore ER folding capacity and mitigate stress [7]. Accumulating evidence based on in vivo and in vitro studies has demonstrated that ER stress is a novel causative factor of pancreatic beta-cell dysfunction and death in the pathogenesis of T2DM [9,10,11]
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